Editorial [Hot Topic: New Approaches to HIV-1 Inhibitor and Vaccine Design (Executive Editor: Lai-Xi Wang)]

AIDS is caused by the infection of the human immunodeficiency virus (HIV). There are two fronts in combating the worldwide epidemic of HIV/AIDS. On the one hand, the emergence of drug-resistant viruses urges the development of new anti-viral drugs that work on a mechanism of action different from those of currently available drugs; on the other hand, the control of the expanding epidemic will eventually rely on an effective preventive HIV vaccine. This special issue consists of seven excellent review articles that focus on new approaches toward HIV inhibitor and vaccine design. The first three articles discuss some most exciting advances in HIV inhibitors that may be further developed as anti-HIV therapeutics. Dr. Nouri Neamati and co-workers [1] from University of Southern California provides an outstanding review on inhibitors targeting HIV integrase (IN), an essential enzyme for HIV replication. The authors highlight the preclinical and clinical studies of the first generation beta-diketo compounds as IN inhibitors and put a special emphasis on advances in the design of the second generation IN inhibitors with improved pharmacokinetic and metabolic properties. Dr. Shibo Jiang and co-workers [2] from the New York Blood Center focuses on another type of HIV inhibitor that targets HIV entry. A beautiful story is given on how a class of polypeptide inhibitors that block gp41-mediated membrane fusion was first discovered, which eventually led to the development of the new anti-HIV drug enfuvirtide (Fuzeon or T-20). The review is then focused on the efforts in searching for small-molecule compounds to interfere the gp41-mediated fusion processes, which may overcome the problems such as the lack of oral bioavailability associated with T-20 and other polypeptide inhibitors. Recent progress in the screening and discovery of such small-molecule inhibitors targeting gp41 is reviewed. In another excellent review, Dr. Alfredo Garzino-Demo [3] from the University of Maryland's Institute of Human Virology describes the discovery and impact of chemokines and beta-defensins as natural HIV-suppressing factors that are produced by host cells. The importance of these host-derived natural factors in battling HIV infection is well discussed. Heavy glycosylation is a strong defense mechanism that HIV has evolved to evade immune attacks. However, compelling experimental data suggest that the carbohydrate antigens on HIV envelope glycoproteins are also valuable targets for antiviral agents and vaccines. Two reviews in this special issue have focused on HIV carbohydrates. Dr. Daniel Ratner (Boston University) and Dr. Peter Seeberger (ETH) [4] provides a timely review on the development of carbohydrate microarrays as tools in searching for HIV-1 gp120-binding proteins specific for the viral carbohydrate antigens. The potential of the developed carbohydrate microarrays in HIV glycobiology is nicely demonstrated by effectively detecting those gp120-binding proteins including DC-SIGN, CD4, 2G12, cyanovirion, and scytovirin. In another timely review, Dr. Thomas Kieber-Emmons and co-workers [5] from University of Arkansas Medical Sciences discuss the issues of defining HIV carbohydrate antigens for vaccine design. In particular, the authors provide an excellent highlight of their own work on molecular design of peptide carbohydrate mimotopes capable of eliciting neutralizing antibodies to recognize HIV carbohydrate antigens. The peptide mimotope approach has a great potential to overcome the weak immunogenicity of HIV carbohydrate antigens. Human monoclonal antibodies capable of neutralizing a broad range of HIV-1 isolates are of great therapeutic potential and also provide an ideal template for HIV vaccine design. However, broadly neutralizing antibodies are rare in infected individuals and are difficult to elicit by active immunization. Dr. Mei-Yun Zhang and Dr. Dimiter Dimitrov [6] from the National Cancer Institute provide an excellent overview on recent advances in identifying neutralizing antibodies targeting HIV envelope glycoproteins gp120/gp41. The review focuses on several new approaches, including sequential antigen panning and competitive antigen panning methods, in identifying neutralizing antibodies. Valuable discussions on the mechanism of the exceptional neutralizing activities of an array of identified neutralizing antibodies are given. Finally, In connection with effective immunogen design, Dr. Richard Wyatt and Dr. Sanjay Phogat [7] from the National Institutes of Health's Vaccine Research Center provide an outstanding review on our current understanding of the structure and function of HIV envelope glycoproteins........